Process for the preparation of 6-methyl-3beta,5alpha,17alpha - trihydroxy - 20 - cyclic ketal pregnane derivative



United States Patent US. Cl. 260239.55 1 Claim ABSTRACT OF THE DISCLOSURE Process for preparing a 6,8-methyl,3,8,5u,17u-trihydroxy 20-cyclic ketal pregnane derivative comprising reacting a 3fi-hydroxyor a 3p-acyloxy-16-methylpregna-5,16-diene- 20-one with hydrogen peroxide under alkaline conditions followed by acylation to provide the 3 3-acyloxy-16a,17aepoxy -16B-methyl-pregn-5-en-20-one, treating the 160:, 17a-epoxide compound with a hydrogen halide to cleave the epoxy group with formation of a Not-hydroxy group, condensing the resulting steroid with an alkane diol to form the corresponding ZO-cyclic ketal derivative, treating said 20-cyclic ketal derivative with an organic per-acid to form the corresponding 5u,6a-epoxide of said 20-cyclic ketal derivative and treating said 5tx,6a-epoxide with a methyl-magnesium halide followed by alkaline hydrolysis to cleave the 5a,6tt-epoxide group and provide the corresponding 6B-methyl,3fi,5a,17a-trihydroxy-20-cyclic ketal.

This application is continuation of application Ser. No. 33,642 filed June 3, 1960, now abandoned.

This invention is for improvements in or relating to the preparation of organic compounds and has particular reference to a process for the preparation of a 20-cyclic ketal derivative of 36,5,l7ac-tl'ihYdI'OXY-6fi methyl l6- methylene-Sa-pregnan-20-one having the general Formula 1 below.

This compound is of value as an intermediate in the preparation of compounds with progestational properties. Thus for example it may be converted into Net-hydroxy and 170: acyloxy-6a-methyl-16-methylenepregn-4-ene-3, ZO-diones which compounds possess outstanding progestational properties.

For this purpose the ketal group at C is removed from the product of the invention. Hydrolysis of the resulting 3 acetoxy 5a-17a-dihydroxy-6fi-methyl-16-methylene- 5a-pregnan-20-one yields the corresponding 3,5,17-triol- 20-one. Oxidation of the last compound gives 5a,17u-dihydroxy 6/3 methyl l6 methyIene-Sa-pregnane-3,20- dione. Dehydration of the last compound at C and epimerisation of the methyl group at C gives 17a-hydroxy- 6a methyl 16-methylene-pregn-4-ene-3,20-dione which passes into the active progestational compound on acetylation at C According to the present invention there is provided a process for the preparation of a 20-cyclic ketal derivative 3,452,006 Patented June 24, 1969 of 313,5,I7a-trihydroxy-6fl-methyl-16-methylene-5ot pregnan-20-one having the formula (where n=2 or 3) which process comprises reacting a Zip-hydroxy or BB-acyloxy-l6-methylpregna-5,16-dien-20- one having the general formula C OMe Me I Me \J (III) (where R is an acyl group containing up to 10 carbon atoms), reacting the 16a,17a-epoxide with hydrogen bromide or hydrogen iodide, reduetively treating if desired the resulting material to give a 3B-acyloxy-l7a-hydroxy- 16-methylenepregn-5-en-20-one having the general formula COMe Mel (where R is an acyl group containing up to 10 carbon atoms), reacting the 3,8-acyloxy-17a-hydroxy-lG-methylenepregn-S-en-ZO-one with an al'kane diol to form its 20- cyclic ketal derivative having the general formula (where R is an acyl group containing up to 10 carbon atoms and n=2 or 3), reacting the 20-cyclic ketal derivative with an organic per-acid to form a 50,6oc-6POXid6 having the general formula (where R is an acyl group containing up to 10 carbon atoms and n=2 or 3), and treating the 5a,6u-epoxide with a methylmagnesium halide followed by alkaline hydrolysis.

The 17a-hydroxy compounds designated by Formulae I, IV, V and VI originally believed to be 16-methyl compounds are now found to possess a methylene group at the 16-position.

In carrying out the process of this invention the 3 8- hydroxy or 3fl-acyloxy-l6-methylpregna-S,16-dien-20-one (II) is converted into the 16a,17a-epoxide by reaction with a peroxidising agent under alkaline conditions, and in particular by reaction with alkaline hydrogen peroxide in a water-miscible organic solvent, such for example as methanol or ethanol, at temperatures between 0 C. and 100 C. and preferably at the reflux temperature of the reaction mixture. Other peroxidising agents such, for example, as tert.-butyl hydroperoxide under alkaline conditions may also be employed.

The 16a,17a-epoxide (III) so formed is obtained as the free 3-hydroxy derivative (III; R=H). It is converted into the 3fi-acyloxy derivative (III; R=acyl), and preferably into the Sfi-acetoxy derivative, by acylation for example with acetic anhydride/ pyridine, which is a method well known to those skilled in the art.

The 3fl-acyloxy derivative (III; where R is acyl) is preferably treated with hydrogen bromide which may be added in solution in a lower aliphatic acid such as acetic acid to the Bfi-acyloxy derivative, preferably dissolved in a mixture of a lower aliphatic acid such as acetic acid and an inert organic solvent such as benzene at a temperature which is preferably in the region of 0 C. The material so obtained may be isolated from the mixture by known methods. Alternatively hydrogen iodide may be employed and may be added in aqueous solution to the epoxide (III; where R is acyl) dissolved in a water-miscible organic solvent, such for example as dioxan, at a temperature in the region of 0 C. Care must be exercised in this operation, which must additionally be carried out speedily and preferably in the absence of light.

When reductive treatment of the material so obtained is desired it may be carried out by a process of catalytic reduction employing a catalyst such as Raney nickel in an organic solvent such as acetone at the ambient temperature. The product obtained is the 17a-hydroxy-16- methylene derivative (IV).

Conversion of the resulting 3fl-acyloxy-17a-hydroxy- 16-methylenepregn-S-en-ZO-one into the 20-cyclic ketal derivative (V; Where R is acyl) is performed by treating the intermediate (IV) with an alkane diol which may be ethane-1,2-diol or propane-1,3-diol in a Water-immiscible organic solvent such as benzene in the presence of a catalytic quantity of an acidic catalyst such as toluene-p-sulphonic acid at the reflux temperature of the reaction mixture in an appropriate apparatus such as the Dean-Stark apparatus which permits removal of water formed in the reaction.

Conversion of the resulting 20-ketal derivative (V) into the 5a,6ot-ep0xide (VI; where R=acyl) may be performed by reaction with peracetic, perbenzoic or monoperphthalic acid in an inert organic solvent such as benzene, chloroform, ether, or mixtures of such inert solvents. The reaction is preferably performed at temperatures between 20 C. and +30 C. and conveniently at ca. 0 C. As known to those skilled in the art, such epoxidation invariably results in the formation of a mixture of 5a,6aand 5,8,6B-epoxides, from which the required 51x, 6u-epoxide may be separated by a process of fractional crystallisation, for which purpose a solvent such as methanol is conveniently employed.

Conversion of the epoxide (VI; where R=acyl) into the desired 3B,5,17a-trihydroxy 6B methyl 16 methylene- 5a-pregnan-20-one (I) is preferably effected by treatment with methylmagnesium bromide or iodide in an inert water-free organic solvent such as diethyl ether, dibutyl ether, benzene, toluene, tetrahydrofuran, or in mixtures of such solvents at a temperature preferably between 20 C. and C.

Following is a description by way of example of methods of carrying the invention into effect.

EXAMPLE 1 3fl-hydroxy-16a,17a-epoxy-16B-methylpregn-5-en-20-one Hydrogen peroxide (100 vol.; ml.) was added dropwise to a refluxing solution of 3 fl-acetoxy-l6-methylpregn- 5,16-dien-20-one (60 g.) in ethanol (600 ml.) and aqueous sodium hydroxide (40%; 30 ml.). The mixture was then heated under reflux for 20 minutes, cooled and the resultant solid was collected by filtration and crystallised from acetone/hexane to give 3fl-hydroxy-16a,Not-epoxy- 16fi-methylpregn-5-en-20-one as prisms, M.P. 189 to 191 (1., [(11 --16 (c., 0.64 in chloroform) The above 3-hydroxy compound (61 g.) was dissolved in pyridine (250 ml.) and acetic anhydride (250 ml.) and warmed on the steam-bath for 1 hour. The solution was cooled, poured into a large excess of water and the product was collected by filtration. Crystallization from methanol gave 3;8-acetoxy-l6u,17a-epoxy 16 8 methylpregn- 5-en-20-one as blades, M.P. 179 to 181 0., --17 (c., 0.78 in chloroform).

3,8-acetoxy-17 a-hydroxy-16-methylenepregn-5 -en-20-one V; R=CH3 3,8-acstoxy-16u,17a-epoxy-1dfl-methylpregn 5 en 20 one (III; R=CH CO) (63 g.) was dissolved in glacial acetic acid (1 l.) and benzene (1 l.) and cooled in ice/ water. A solution of hydrogen bromide in acetic acid (50%; 100 ml.) was then added and the solution was stirred at 0 C. for 30 minutes. An equal volume of water was then added and the mixture was extracted with chloroform. The chloroform extracts were washed with water, aqueous sodium bicarbonate and dried (Na SO and the solvent was removed under reduced pressure. The residue was dissolved in acetone (2 1.), Raney nickel (300 m1. suspension) added and the reaction mixture stirred at room temperature for 4 hours after which it was filtered through Hyflo and the residue was washed with hot acetone. The filtrate was then evaporated under reduced pressure and crystallised from methanol. The product was 3fi-acetoxy 17a-hydroxy-16 methylenepregn-5-en-20- one, M.P. 184 to 186 or 206 to 208 C., [M 126 (c., 0.36 in chloroform).

3 p-acetoxy-20,20-ethylenedioxy- 17 a-hydroxy-l 6-methylenepregn-S-ene (V; R=CH CO, m=2) bined extracts were washed with water, and dried H (Na SO Removal of the solvent under reduced pressure and crystallisation of the residue from methanol (+1 drop pyridine) gave 3fi-acetoxy-ZO,20-ethylenedioxy 17u-hydroxy-16-methylenepregn-5-ene as needles, M.P. 183 to 184 C., 101 (c., 0.33 in chloroform+1 drop pyridine).

3fi-acetoxy-5, 6a-epoxy-20,20-ethylenedioxy-17a-hydroxyl6-methylene-5a-pregnane (VI; R=CH CO, n=2) An ethereal solution of monoperphthalic acid (1.0 N; 300 ml.) was added to 3B-acetoxy-20,20-ethylenedioxyl7u-hydroxyl6-methylenepregn-5-ene (V; R=CH CO, n=2) in chloroform (200 ml.) and the reaction mixture kept at 0 C. for 4 hours. The mixture was then washed with dilute sodium hydroxide solution, water and dried (Na SO Removal of the solvent under reduced pressure and crystallisation of the residue from methanol (+1 drop pyridine) gave 3,6-acetoxy-5,6a-epoxy-20,20 ethylenedioxy-17a-hydroxy-16-methylene-5a-pregnane as plates, M.P. 215 to 217 C., [M l01 (c., 0.29 in chloroform-H drop pyridine).

20,20-ethylenedioxy-3 3,5,17ot-trihydroxy-6fi-methyl- 16-methylene-5e-pregnane (I, n'=2) Methylmagnesium iodide was prepared in the usual manner from magnesium (2.8 g.), methyl iodide g.) and anhydrous ether (100 ml.). 3;3-acetoxy-5,6u-epoxy- 20,20 ethylenedioxy 17a hydroxy-16methylene-5apregnane (VI; R=CH CO, 11:2) (3.9 g.) in anhydrous benzene (200 ml.) was added and the ether was removed by distillation. The reaction mixture was then stirred under reflux for 3 hours. After cooling, the mixture was decomposed with aqueous ammonium chloride and the product was isolated by extraction with ether. The combined extracts were washed with water and dried (Na- 50 and the solvent was removed under reduced pressure. crystallisation of the residue from acetone/ hexane gave 36,5,17a-trihydroxy-20,20-ethylenedioxy-6pmethyl-16-methylene-5a-pregnane,

EXAMPLE 2 3fi-acetoxy-17a-hydroxy-16-methylenepregn-5-en-20-one (IV; R=CH CO) 35 acetoxy 16 8 methyl-16a,l7a-epoxypregn-5-en- 20-one (III; R=CH CO) (17 g.), prepared as given in Example 1, was dissolved in dioxan (750 ml.), cooled to 0 C. and treated with aqueous hydrogen iodide (50%; 125 ml.) in the absence of light. After being stirred at 0 C. for 30 minutes in the absence of light, the reaction mixture was added dropwise with stirring to water (2.5 1.), stirring being continued until the product coagulated. The mixture was then filtered, the residue being washed with water and dried. The iodinated material was removed by dissolving in acetone (750 ml.) adding Raney nickel g.) and stirring at room temperature for 30 minutes. Methylene dichloride was then added, the mixture filtered through Hyflo and the residue was washed with methylene dichloride. Removal of the solvent under reduced pressure and crystallisation of the residue from methanol gave 3fl-acetoxy-17a-hydroxy-16-methylenepregn-5-en-20-one, M.P. to 182 C. alone and on admixture with a sample prepared according to Example 1.

3 5,5, 17 ot-trihydroxy-20,20-ethylenedioxy-6B-methyl-16- methyIene-Sa-pregnane Treatment of 3fl-acetoxy-17u-hydroxy-16-methylenepregn-5-en-20-one (IV; R=CH CO) according to the steps outlined in Example 1 gave 3,B,5,17u-trihydroxy- 20,20 ethylenedioxy 6p-methyl-16-methylene-5a-pregname.

What is claimed is:

1. A process for the preparation of a 3/3-5a,17a-trihydroxy-6 8-methyl-20-cyclic ketal derivative of a steroid compound having the formula C OMe where R is selected from the group consisting of hydrogen and an acyl group derived from a hydrocarbon carboxylic acid containing up to 10 carbon atoms, comprising reacting a steroid compound of said formula with'hydrogen peroxide under alkaline conditions followed by acylation with an acylating agent providing an acyl group as defined above to form a 3fl-acyloxy-16a,l7a-epoxy compound of the formula where R is an acyl group as defined above, treating the 16a,17a-epoxy compound with a hydrogen halide to cleave the epoxy group and provide a 17a-hydroxy group, subjecting the resulting 17a-hydroxy steroid compound to reductive treatment employing Raney nickel in an organic solvent, condensing the resulting steroid compound with an alkane diol having from 2 to 3 carbon atoms to form the 20-cyclic ketal derivative, treating said 20-cyclic ketal derivative with an organic per-acid selected from the group consisting of pera-cetic, perbenzoic and monoperthalic acids to form a 5a,6u-epoxy compound with methyl magnesium halide followed by alkaline hydrolysis to provide the said 6fi-methyl-3B,5a,17tx-trihydroxy- 20-cyclic ketal pregnane derivative.

References Cited UNITED STATES PATENTS 3,312,692 4/1967 Olive et al.

ELBERT L. ROBERTS, Primary Examiner.

U.S. Cl. X.R. 260397.4 

